This Competitive Revision Application is in response to Notice Number: NOT-OD-09-058 and Notice Title: NIH Announces the Availability of Recovery Act Funds and is proposed as a competitive supplement to our current R01 grant DA 13519, titled "Development of Novel Therapies for Methamphetamine Abuse" (FOA is PA07070). Currently, there is no treatment available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. We request 2 years of support to expand the scope of our specific aims and accelerate the preclinical development of a clinical candidate for testing in human subjects. Recently, we have identified a novel structure (GZ-793A) that was not described in the original funded application. Among all the compounds screened through the neurochemical assays focusing on compounds which potently and selectively interact with the vesicular monoamine transporter-2 (VMAT2), GZ-793A has exhibited the greatest potency and specificity in decreasing responding for intravenous methamphetamine. GZ-793A produced a complete blockade of methamphetamine self-administration (SA) in rats, without any alteration in responding for sucrose, i.e., it specifically decreases methamphetamine SA. The physicochemical properties of GZ-793A provides enhanced solubility and drugability relative to the majority of compounds initially proposed in the funded project. In this Competitive Revision Application, we propose to optimize the chemical structure of GZ- 793A to ensure that several compounds of this promising new class are available as backups for the lead compound GZ-793A. We will evaluate this novel series of optimized compounds described in this Competitive Revision Application in the neurochemical assays to obtain a potent and selective VMAT2 inhibitor as additional structurally optimized lead compounds. These lead compounds will be evaluated in the methamphetamine SA assay following acute and repeated administration. We also propose to evaluate our current lead compound GZ-793A and the 3-4 additional lead compounds emerging from this research in comprehensive pharmacokinetic evaluations to assess their drugability, as well as their ability to decrease methamphetamine SA following oral administration. Our goal by the end of the 2nd year of the Competitive Revision Application is to have identified a drugable, orally bioavailable, clinical candidate to move to comprehensive toxicological evaluation for preparation of an Investigational New Drug application (IND) to the FDA. This project will stimulate the economy through the hiring of 4 additional postdoctoral fellows and 2 additional technical staff, and through the procurement of additional equipment to conduct the studies. This project evaluating a complementary series of methamphetamine blockers will be completed within 2 years. Concurrently, the parent grant will continue as originally proposed, such that no budgetary changes for the remainder of the parent project are anticipated. The new funds will accelerate our productivity and allow us to pursue this new, but related, line of investigation toward the outcome of obtaining a clinical candidate for the treatment of methamphetamine abuse. PUBLIC HEALTH RELEVANCE: This Competitive Revision Application is in response to Notice Number: NOT-OD-09-058 and Notice Title: NIH Announces the Availability of Recovery Act Funds and is proposed as a competitive supplement to our current R01 grant DA 13519, titled "Development of Novel Therapies for Methamphetamine Abuse" (FOA is PA07070). Currently, there is no treatment available for methamphetamine abuse. The overall objective of this project is to provide a clinical candidate for the treatment of methamphetamine abuse. Recently, we identified a novel structure (GZ-793A) which potently and selectively interacts with the vesicular monoamine transporter-2 and exhibits potency and specificity in decreasing responding for intravenous methamphetamine in an animal model. We propose to optimize the chemical structure of GZ- 793A, provide additional leads that are drugable orally-bioavailable clinical candidates and bring them to comprehensive toxicological evaluation for preparation of an Investigational New Drug application (IND) to the FDA.